Menstrual cycle phase and its association with COVID-19 vaccine side effects and subsequent infection: A study of period tracking app users.

Despite known hormonal influences on immune function, the impact of menstrual cycle phase on vaccine side effects and subsequent infection risk remains unexplored. We used prospectively tracked cycle data from the period tracking app, Clue, matched with an in-app vaccine survey conducted between November 2021 and February 2022. In a sample of 1,474 cycling women, we compared reported side effect and post-vaccination infection outcomes of women vaccinated in the estrogen-dominant follicular phase of their cycle, with those vaccinated in the progesterone-dominant luteal phase. Side effect presence, severity and number were analysed using binary, ordinal, and negative binomial regression models respectively. Post vaccination time to infection (over 67-372 days of follow-up) was compared between the two groups using Wilcoxon rank-sum test and a Cox proportional hazards model. Follicular-phase vaccination was associated with 35% higher odds of reporting any side effects (OR: 1.35, 95% CI: 1.05-1.66) compared to luteal-phase vaccination. The association remained significant after excluding individuals vaccinated during the bleed phase, and the perimenstrual phase, indicating that hormonal environment, rather than inflammation caused by menstruation or premenstrual symptoms, may drive the association. Median time to infection was 35 days longer for those vaccinated in the follicular phase (Follicular: 200 (140,237) Luteal 165 (107, 2107), p = 0.05), suggesting potential longer-lasting protection from the vaccine. These findings suggest that menstrual cycle phase should be considered when studying sex-based immune differences and may inform future research on vaccination timing and personalised health strategies.